TWI789109B - Anti-biological adhesion copolymer and method of preparing the same - Google Patents
Anti-biological adhesion copolymer and method of preparing the same Download PDFInfo
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Abstract
Description
本發明是有關於一種共聚物及其製備方法，特別是指一種抗生物沾黏共聚物及其製備方法。The present invention relates to a copolymer and its preparation method, in particular to an anti-bioadhesion copolymer and its preparation method.
中華民國專利公告第629320B揭示一種抗生物分子沾黏材料及其製造方法。該抗生物分子沾黏材料包含基材及藉由共價鍵結固定在該基材的表面的塗佈層。該基材為玻璃、金屬、金屬氧化物、陶瓷、矽晶圓或塑膠。該塗佈層包含共聚物，且該共聚物由具有環氧基的單體和具有雙離子官能基的單體所聚合構成，其中，該雙離子官能基為磺基甜菜鹼基或羧基甜菜鹼基。該生物分子例如纖維蛋白元、血小板、紅血球、組織細胞或大腸桿菌。Republic of China patent announcement No. 629320B discloses an anti-biomolecule adhesion material and its manufacturing method. The anti-biomolecule adhesion material comprises a base material and a coating layer fixed on the surface of the base material through covalent bonding. The substrate is glass, metal, metal oxide, ceramic, silicon wafer or plastic. The coating layer comprises a copolymer, and the copolymer is composed of a monomer having an epoxy group and a monomer having a diionic functional group, wherein the diionic functional group is sulfobetaine or carboxybetaine base. Such biomolecules are for example fibrinogen, platelets, erythrocytes, histiocytes or Escherichia coli.
該抗生物分子沾黏材料的製造方法包括步驟(1)，提供基材；步驟(2)，進行活化程序，在該基材表面導入官能基，該官能基包含羥基、胺基和硫醇基；步驟(3)，提供共聚物，該共聚物由具有環氧基的單體和具有雙離子官能基的單體所聚合構成；及，步驟(4)，進行反應，使該共聚物和該基材表面的官能基產生共價鍵，形成抗生物分子沾黏材料，其中，該反應是在酸鹼值1~5或8~11的環境下進行。The manufacturing method of the anti-biomolecule adhesion material includes step (1), providing a substrate; step (2), performing an activation procedure, introducing a functional group on the surface of the substrate, and the functional group includes a hydroxyl group, an amino group and a thiol group Step (3), providing a copolymer, the copolymer is formed by polymerizing a monomer with an epoxy group and a monomer with a diionic functional group; and, step (4), reacting to make the copolymer and the The functional group on the surface of the substrate produces a covalent bond to form an anti-biomolecular adhesion material, wherein the reaction is carried out in an environment with a pH value of 1-5 or 8-11.
雖然該共聚物能夠賦予該基材具有抗生物分子沾黏的優點，然而，該共聚物中的環氧基為不穩定的基團，致使該共聚物易發生自交聯反應，而使得該共聚物與該基材的表面官能基的接枝效果不佳，進而影響該抗生物分子沾黏材料的抗生物分子沾黏性。此外，因該共聚物發生自交聯反應，導致有團聚的黏著塊狀物產生，而不利於該共聚物的操作性，致使較難均勻地接枝在該基材上。基於上述，而有必要對該共聚物進行改善。Although the copolymer can endow the base material with the advantage of anti-biomolecular adhesion, yet, the epoxy group in the copolymer is an unstable group, which makes the copolymer prone to self-crosslinking reaction, so that the copolymerization The grafting effect of the substance and the surface functional group of the base material is not good, thereby affecting the anti-biomolecule adhesion of the anti-biomolecule adhesion material. In addition, due to the self-crosslinking reaction of the copolymer, agglomerated sticky lumps are produced, which is not conducive to the handling of the copolymer, making it difficult to graft uniformly on the substrate. Based on the above, it is necessary to improve the copolymer.
因此，本發明的第一目的，即在提供一種抗生物沾黏共聚物。Therefore, the first object of the present invention is to provide an anti-bioadhesive copolymer.
於是，本發明抗生物沾黏共聚物，包含：式(I)所示的結構單元，及式(II)所示的結構單元。其中，該式(I)所示的結構單元與式(II)所示的結構單元的莫耳比例範圍為20：80至40：60；
本發明的第二目的，即在提供一種抗生物沾黏共聚物的製備方法。The second purpose of the present invention is to provide a preparation method of an anti-bioadhesion copolymer.
於是，本發明抗生物沾黏共聚物的製備方法，包含以下步驟：使式(a)所示的化合物的雙鍵與式(b)所示的化合物的雙鍵進行反應，
本發明的功效在於：透過該式(I)所示的結構單元及該式(II)所示的結構單元，本發明抗生物沾黏共聚物的醛基具有穩定性而不易產生自交聯反應，從而有利於接枝於表面具有胺基的基材上，以至於賦予該基材具有良好的抗生物沾黏性。The effect of the present invention is that: through the structural unit shown in the formula (I) and the structural unit shown in the formula (II), the aldehyde group of the anti-bioadhesive copolymer of the present invention has stability and is not easy to produce self-crosslinking reaction , so as to facilitate grafting on the substrate with amine groups on the surface, so as to endow the substrate with good anti-bioadhesive properties.
以下將就本發明進行詳細說明。The present invention will be described in detail below.
[抗生物沾黏共聚物][Anti-bioadhesive copolymer]
該抗生物沾黏共聚物包含式(I)所示的結構單元及式(II)所示的結構單元。其中，該式(I)所示的結構單元與式(II)所示的結構單元的莫耳比例範圍為20：80至40：60；
在本發明的一些實施態樣中，該R 1及該R 2為甲基。 In some embodiments of the present invention, the R 1 and the R 2 are methyl.
在本發明的一些實施態樣中，該X為O。In some embodiments of the present invention, the X is O.
在本發明的一些實施態樣中，較佳地，該式(I)所示的結構單元與式(II)所示的結構單元的莫耳比例為20：80。In some embodiments of the present invention, preferably, the molar ratio of the structural unit represented by the formula (I) to the structural unit represented by the formula (II) is 20:80.
[抗生物沾黏共聚物的製備方法][Preparation method of anti-bioadhesion copolymer]
該抗生物沾黏共聚物的製備方法，包含以下步驟：使式(a)所示的化合物的雙鍵與式(b)所示的化合物的雙鍵進行反應，
在本發明的一些實施態樣中，該式(a)所示的化合物為CH 2=C(CH 3)-C(O)-O-CH 2-C(O)H。在本發明的一些實施態樣中，該CH 2=C(CH 3)-C(O)-O-CH 2-C(O)H的製備方法是使甲基丙烯酸羥乙酯的羥基經氧化反應轉變為醛基而製得。在本發明的一些實施態樣中，該CH 2=C(CH 3)-C(O)-O-CH 2-C(O)H的製備方法是使甲基丙烯酸縮水甘油酯的環氧基經氧化反應轉變為醛基而製得。 In some embodiments of the present invention, the compound represented by the formula (a) is CH 2 ═C(CH 3 )-C(O)-O-CH 2 -C(O)H. In some embodiments of the present invention, the CH 2 =C(CH 3 )-C(O)-O-CH 2 -C(O)H is prepared by oxidizing the hydroxyl group of hydroxyethyl methacrylate Reaction into the aldehyde and the system. In some embodiments of the present invention, the preparation method of CH 2 =C(CH 3 )-C(O)-O-CH 2 -C(O)H is to make the epoxy group of glycidyl methacrylate It is prepared by oxidation reaction into aldehyde group.
在本發明的一些實施態樣中，該式(b)所示的化合物為磺基甜菜鹼甲基丙烯酸酯(sulfobetaine methacrylate)。In some embodiments of the present invention, the compound represented by the formula (b) is sulfobetaine methacrylate.
在本發明的一些實施態樣中，較佳地，該式(a)所示的化合物與該式(b)所示的化合物的莫耳比例為20：80。In some embodiments of the present invention, preferably, the molar ratio of the compound represented by the formula (a) to the compound represented by the formula (b) is 20:80.
在本發明的一些實施態樣中，該反應是在氮氣環境下進行。在本發明的一些實施態樣中，該反應的溫度為60℃。在本發明的一些實施態樣中，該反應的時間為6小時。In some embodiments of the invention, the reaction is performed under nitrogen atmosphere. In some embodiments of the invention, the temperature of the reaction is 60°C. In some embodiments of the present invention, the reaction time is 6 hours.
本發明將就以下實施例作進一步說明，但應瞭解的是，該實施例僅為例示說明之用，而不應被解釋為本發明實施之限制。The present invention will be further described with reference to the following examples, but it should be understood that these examples are for illustrative purposes only and should not be construed as limitations on the implementation of the present invention.
實施例1Example 1
將0.3121克(2.44mmol)的CH 2=C(CH 3)-C(O)-O-CH 2-C(O)H、0.02克的偶氮二異丁腈及11.377克的甲醇混合，形成第一溶液。將2.722克(9.74mmol)的磺基甜菜鹼甲基丙烯酸酯及3.792克的水混合，形成第二溶液。接著，將該第一溶液與該第二溶液混合，且於氮氣環境下加熱至60℃，並在300rpm的攪拌速率下進行6小時的反應，形成包含抗生物沾黏共聚物的第一混合物。將該混合物置於0℃的冰水浴中10分鐘以終止反應，得到一第二混合物，其中，該第二混合物包含黏稠物及未反應的溶液，且該黏稠物包括該抗生物沾黏共聚物。自該第二混合物中去除該未反應的溶液，接著，加入甲醇，使該抗生物沾黏共聚物自該黏稠物中析出，然後，進行過濾，獲得該抗生物沾黏共聚物。依序利用一台真空烘箱及一台冷凍乾燥機，對該抗生物沾黏共聚物進行乾燥處理。 0.3121 g (2.44 mmol) of CH2 =C( CH3 )-C(O)-O- CH2 -C(O)H, 0.02 g of azobisisobutyronitrile and 11.377 g of methanol were mixed to form first solution. 2.722 grams (9.74 mmol) of sulfobetaine methacrylate and 3.792 grams of water were mixed to form a second solution. Next, the first solution and the second solution were mixed, heated to 60° C. under a nitrogen atmosphere, and reacted at a stirring rate of 300 rpm for 6 hours to form a first mixture comprising an anti-bioadhesive copolymer. The mixture was placed in an ice-water bath at 0°C for 10 minutes to terminate the reaction, and a second mixture was obtained, wherein the second mixture contained viscous and unreacted solution, and the viscous contained the anti-bioadhesive copolymer . Remove the unreacted solution from the second mixture, then add methanol to precipitate the anti-bioadhesive copolymer from the viscous material, and then filter to obtain the anti-bioadhesive copolymer. The anti-biological adhesion copolymer is dried by using a vacuum oven and a freeze dryer in sequence.
實施例2至實施例3Example 2 to Example 3
實施例2至實施例3的製備方法與實施例1大致相同，差別主要在於：在該實施例2中，使用0.4681克(3.654mmol)的CH 2=C(CH 3)-C(O)-O-CH 2-C(O)H及2.382克(8.526mmol)的磺基甜菜鹼甲基丙烯酸酯，其中，該CH 2=C(CH 3)-C(O)-O-CH 2-C(O)H與該磺基甜菜鹼甲基丙烯酸酯的莫耳比例為30：70；在該實施例3中，使用0.6242克(4.872mmol)的CH 2=C(CH 3)-C(O)-O-CH 2-C(O)H及2.041克(7.308mmol)的磺基甜菜鹼甲基丙烯酸酯，其中，該CH 2=C(CH 3)-C(O)-O-CH 2-C(O)H與該磺基甜菜鹼甲基丙烯酸酯的莫耳比例為40：60。 The preparation method of Example 2 to Example 3 is roughly the same as that of Example 1, the main difference is that in this Example 2, 0.4681 g (3.654 mmol) of CH 2 =C(CH 3 )-C(O)- O-CH 2 -C(O)H and 2.382 g (8.526 mmol) of sulfobetaine methacrylate, wherein, the CH 2 =C(CH 3 )-C(O)-O-CH 2 -C The molar ratio of (O)H to the sultaine methacrylate is 30:70; in this Example 3, 0.6242 grams (4.872 mmol) of CH 2 =C(CH 3 )-C(O )-O-CH 2 -C(O)H and 2.041 grams (7.308mmol) of sulfobetaine methacrylate, wherein, the CH 2 =C(CH 3 )-C(O)-O-CH 2 The molar ratio of -C(O)H to the sulfobetaine methacrylate is 40:60.
結構分析：利用紅外線光譜儀及核磁共振光譜儀，對實施例1或/及實施例3的抗生物沾黏共聚物進行量測，結果如圖1及圖2所示。Structural analysis: The anti-bioadhesive copolymer of Example 1 or/and Example 3 was measured by infrared spectrometer and nuclear magnetic resonance spectrometer, and the results are shown in FIG. 1 and FIG. 2 .
參閱圖1，於波數為1047cm -1處的訊號峰為磺基甜菜鹼甲基丙烯酸酯的磺酸基(-SO 3H)、於波數為1648cm -1處的訊號峰為磺基甜菜鹼甲基丙烯酸酯的四級胺、於波數為1700cm -1處的訊號峰為磺基甜菜鹼甲基丙烯酸酯的酯基的羰基(-C=O)、於波數為2989cm -1處的訊號峰為CH 2=C(CH 3)-C(O)-O-CH 2-C(O)H的醛基的C-H、於波數為1776cm -1處的訊號峰為CH 2=C(CH 3)-C(O)-O-CH 2-C(O)H的醛基的羰基(-C=O)，及於波數為1719cm -1處的訊號峰為CH 2=C(CH 3)-C(O)-O-CH 2-C(O)H的酯基的羰基(-C=O)，此表示本發明抗生物沾黏共聚物確實被獲得。 Referring to Figure 1, the signal peak at wavenumber 1047cm -1 is the sulfonic acid group (-SO 3 H) of sulfobetaine methacrylate, and the signal peak at wavenumber 1648cm -1 is sulfobeet The quaternary amine of alkali methacrylate, the signal peak at the wave number of 1700cm -1 is the carbonyl group (-C=O) of the ester group of sulfobetaine methacrylate, at the wave number of 2989cm -1 The signal peak of the CH 2 =C(CH 3 )-C(O)-O-CH 2 -C(O)H aldehyde group CH, the signal peak at the wave number of 1776cm -1 is CH 2 =C (CH 3 )-C(O)-O-CH 2 -C(O)H carbonyl (-C=O), and the signal peak at the wave number of 1719cm -1 is CH 2 =C( The carbonyl group (-C=O) of the ester group of CH 3 )-C(O)-O-CH 2 -C(O)H indicates that the anti-bioadhesive copolymer of the present invention is indeed obtained.
參閱圖2，於δ=4.55ppm處的訊號峰為CH 2=C(CH 3)-C(O)-O-CH 2-C(O)H的CH 2=訊號，而於δ=3.09ppm處的訊號峰為磺基甜菜鹼甲基丙烯酸酯的-N +(CH 3) 2的氫，此表示本發明抗生物沾黏共聚物確實被獲得。 Referring to Figure 2, the signal peak at δ=4.55ppm is the CH 2 = signal of CH 2 =C(CH 3 )-C(O)-O-CH 2 -C (O)H, and at δ=3.09ppm The signal peak at is the -N + (CH 3 ) 2 hydrogen of sulfobetaine methacrylate, which indicates that the anti-bioadhesive copolymer of the present invention is indeed obtained.
比較例1至比較例2Comparative Example 1 to Comparative Example 2
比較例1至比較例2的製備方法與實施例1大致相同，差別主要在於：在該比較例1中，使用0.1561克(1.218mmol)的CH 2=C(CH 3)-C(O)-O-CH 2-C(O)H及3.062克(10.962mmol)的磺基甜菜鹼甲基丙烯酸酯，其中，該CH 2=C(CH 3)-C(O)-O-CH 2-C(O)H與該磺基甜菜鹼甲基丙烯酸酯的莫耳比例為10：90；在該比較例2中，使用0.9362克(7.308mmol)的CH 2=C(CH 3)-C(O)-O-CH 2-C(O)H及1.361克(4.872mmol)的磺基甜菜鹼甲基丙烯酸酯，其中，該CH 2=C(CH 3)-C(O)-O-CH 2-C(O)H與該磺基甜菜鹼甲基丙烯酸酯的莫耳比例為60：40。 The preparation method of Comparative Example 1 to Comparative Example 2 is roughly the same as that of Example 1, the main difference being that in this Comparative Example 1, 0.1561 grams (1.218 mmol) of CH 2 =C(CH 3 )-C(O)- O-CH 2 -C(O)H and 3.062 g (10.962 mmol) of sulfobetaine methacrylate, wherein, the CH 2 =C(CH 3 )-C(O)-O-CH 2 -C The molar ratio of (O)H to the sultaine methacrylate is 10:90; in this Comparative Example 2, 0.9362 g (7.308 mmol) of CH 2 =C(CH 3 )-C(O )-O-CH 2 -C(O)H and 1.361 g (4.872 mmol) of sulfobetaine methacrylate, wherein the CH 2 =C(CH 3 )-C(O)-O-CH 2 The molar ratio of -C(O)H to the sulfobetaine methacrylate is 60:40.
應用例1Application example 1
利用丙酮清洗1cm x 1cm的矽晶片，然後，以氮氣吹乾，得到經清洗的矽晶片。利用一台紫外光臭氧機(UV Ozone；廠牌：智果整合；型號：UVC10)照射該經清洗的矽晶片的表面30分鐘，以使該經清洗的矽晶片的表面帶有氫氧基，形成具有氫氧基的矽晶片，接著，將該具有氫氧基的矽晶片浸入含有5mL的甲苯及0.872µL的3-氨基丙基三乙氧基矽烷的溶液中，並於37℃下反應30分鐘，使該具有氫氧基的矽晶片的氫氧基與該3-氨基丙基三乙氧基矽烷反應，形成表面具有胺基的矽晶片。A 1 cm x 1 cm silicon wafer was cleaned with acetone, and then dried with nitrogen to obtain a cleaned silicon wafer. Utilize an ultraviolet light ozone machine (UV Ozone; Brand: Zhiguo Integration; Model: UVC10) to irradiate the surface of this cleaned silicon wafer for 30 minutes, so that the surface of this cleaned silicon wafer has hydroxyl groups, Form a silicon wafer with hydroxyl groups, and then immerse the silicon wafer with hydroxyl groups in a solution containing 5 mL of toluene and 0.872 µL of 3-aminopropyltriethoxysilane, and react at 37°C for 30 Minutes, make the hydroxyl groups of the silicon wafer with hydroxyl groups react with the 3-aminopropyltriethoxysilane to form silicon wafers with amino groups on the surface.
將3.0毫克的實施例1的抗生物沾黏共聚物及3.0mL的水混合，形成共聚物溶液，其中，在該共聚物溶液中，該抗生物沾黏共聚物的濃度為1.0mg/mL。將該表面具有胺基的矽晶片浸入該共聚物溶液中，然後，置於一台搖擺烘箱中，且於110rpm旋轉速率下在60℃下反應24小時，形成抗生物沾黏矽晶片。Mix 3.0 mg of the anti-bioadhesion copolymer of Example 1 and 3.0 mL of water to form a copolymer solution, wherein the concentration of the anti-bioadhesion copolymer in the copolymer solution is 1.0 mg/mL. The silicon wafer with amine groups on the surface was immersed in the copolymer solution, and then placed in a rocking oven, and reacted at 60° C. for 24 hours at a rotation speed of 110 rpm to form an anti-bioadhesive silicon wafer.
應用例2至應用例3Application Example 2 to Application Example 3
應用例2至應用例3的製備方法與應用例1大致相同，差別主要在於：在該應用例2中，該抗生物沾黏共聚物為實施例2；在該應用例3中，該抗生物沾黏共聚物為實施例3。The preparation method of application example 2 to application example 3 is roughly the same as that of application example 1, the main difference is: in this application example 2, the anti-bioadhesive copolymer is Example 2; in this application example 3, the anti-bioadhesive copolymer The adhesive copolymer is Example 3.
比較應用例1至比較應用例2Comparative Application Example 1 to Comparative Application Example 2
比較應用例1至比較應用例2的製備方法與應用例1大致相同，差別主要在於：在該比較應用例1中，該抗生物沾黏共聚物為比較例1；在該比較應用例2中，該抗生物沾黏共聚物為比較例2。The preparation method of Comparative Application Example 1 to Comparative Application Example 2 is roughly the same as that of Application Example 1, the main difference being: in this Comparative Application Example 1, the anti-bioadhesive copolymer is Comparative Example 1; in this Comparative Application Example 2 , the anti-bioadhesion copolymer is Comparative Example 2.
[評價項目][evaluation item]
將應用例1至應用例3的抗生物沾黏矽晶片、比較應用例1至比較應用例2的抗生物沾黏矽晶片，及比較應用例8的表面具有胺基的矽晶片進行以下評價。為了清楚說明，以下評價項目的測試流程以應用例1作為代表進行描述。The anti-bioadhesion silicon wafers of Application Example 1 to Application Example 3, the anti-bioadhesion silicon wafers of Comparative Application Example 1 to Comparative Application Example 2, and the silicon wafer having amine groups on the surface of Comparative Application Example 8 were evaluated as follows. For clarity, the test process of the following evaluation items is described using Application Example 1 as a representative.
相對蛋白質吸附率量測：將應用例1的抗生物沾黏矽晶片置於1.0mL的磷酸鹽緩衝生理鹽水(phosphate buffered saline)中，並置於一台37℃的熱風循環烘箱中靜置30分鐘，接著，將該磷酸鹽緩衝生理鹽水移除，並利用磷酸鹽緩衝生理鹽水潤洗該抗生物沾黏矽晶片3次。然後，將該抗生物沾黏矽晶片浸泡於1mL的牛血清白蛋白(Bovine Serum Albumin)溶液中，並放置於一台37℃的熱風循環烘箱中靜置30分鐘，接著，利用定量吸管將該牛血清白蛋白溶液吸出，並利用磷酸鹽緩衝生理鹽水潤洗該抗生物沾黏矽晶片3次。然後，將該抗生物沾黏矽晶片浸泡於1mL的二辛可寧酸(bicinchoninc acid，簡稱BCA)顯影液中，並放置於一台37℃的熱風循環烘箱中靜置30分鐘，形成包含牛血清白蛋白的顯影液，接著，利用定量吸管吸取200µL的該包含牛血清白蛋白的顯影液，並將該包含牛血清白蛋白的顯影液置於96孔盤中，然後，利用一台微量盤式分光光譜儀(Microplate Spectrophotometer；廠牌：BMG LABTECH；型號：SPECTROstar Nano)以波長562nm對該包含牛血清白蛋白的顯影液進行量測，且搭配預先建立好的牛血清白蛋白吸附檢量線，從而計算出該抗生物沾黏矽晶片的表面上的相對蛋白質吸附率。Measurement of relative protein adsorption rate: Place the anti-bioadhesive silicon wafer in Application Example 1 in 1.0 mL of phosphate buffered saline (phosphate buffered saline), and place it in a hot air circulation oven at 37°C for 30 minutes , and then, the phosphate-buffered saline was removed, and the anti-bioadhesive silicon wafer was rinsed 3 times with phosphate-buffered saline. Then, soak the anti-bioadhesive silicon wafer in 1mL of bovine serum albumin (Bovine Serum Albumin) solution, and place it in a hot air circulation oven at 37°C for 30 minutes, then, use a measuring pipette to The bovine serum albumin solution was aspirated, and the anti-bioadhesive silicon chip was rinsed with phosphate-buffered saline for 3 times. Then, the anti-biocinchoninc acid (BCA) developer solution was soaked in 1 mL of bicinchoninc acid (BCA), and placed in a hot air circulation oven at 37°C for 30 minutes to form a The developing solution containing serum albumin, then, use a quantitative pipette to draw 200 µL of the developing solution containing bovine serum albumin, and place the developing solution containing bovine serum albumin in a 96-well plate, and then use a microplate A spectrophotometer (Microplate Spectrophotometer; brand: BMG LABTECH; model: SPECTROstar Nano) was used to measure the developing solution containing bovine serum albumin at a wavelength of 562nm, and with the pre-established bovine serum albumin adsorption calibration line, Thus, the relative protein adsorption rate on the surface of the anti-bioadhesive silicon wafer was calculated.
紅血球貼附量量測：對健康的捐血者進行抽血作業，並將血液輸送至含有檸檬酸鈉(Sodium citrate)抗凝血劑的血袋中，獲得血液樣品。利用離心機對該血液樣品進行離心處理，且該離心處理的離心力為130rcf及時間為10分鐘，並取出下層液。將尺寸為1cm 2的應用例1的抗生物沾黏矽晶片放置於24孔盤(well plate)中，接著，於每個孔中加入1mL的磷酸鹽緩衝生理鹽水(phosphate buffered saline)，然後，放入37℃的培養箱中靜置12小時，接著，自每個孔中移除磷酸鹽緩衝生理鹽水，然後，用磷酸鹽緩衝生理鹽水潤洗三次，接著，於每個孔中加入1mL的上述的下層液，然後，放入37℃的培養箱中靜置1小時，接著，自每個孔中移除該下層液，並用磷酸鹽緩衝生理鹽水潤洗三次，且不可沖洗到該抗生物沾黏矽晶片的表面，以避免將貼附在該抗生物沾黏矽晶片上的血液被沖刷掉，然後，於每個孔中加入1mL的戊二醛溶液(包括戊二醛及磷酸鹽緩衝生理鹽水，且該戊二醛的濃度為2.5wt%)並靜置3小時，接著，自每個孔中移除該戊二醛並用磷酸鹽緩衝生理鹽水潤洗三次，然後，利用拭鏡紙擦乾，獲得待測樣品。利用包含倒立相位差螢光顯微鏡(廠牌：Nexcope；型號：NIB410)的倒立式螢光顯微鏡系統模組(廠牌：Mshot Co.；型號：MSG0)對該待測樣品進行觀測及拍照，然後，利用Image J軟體計算紅血球貼附量。 Measurement of red blood cell attachment volume: Blood draws are performed on healthy blood donors, and the blood is delivered to a blood bag containing sodium citrate (Sodium citrate) anticoagulant to obtain blood samples. The blood sample was centrifuged by a centrifuge with a centrifugal force of 130 rcf and a time of 10 minutes, and the lower layer was taken out. Place the anti-bioadhesion silicon chip of Application Example 1 with a size of 1 cm in a 24-well plate, then add 1 mL of phosphate buffered saline to each well, and then, Put it in an incubator at 37°C for 12 hours, then remove phosphate-buffered saline from each well, then rinse with phosphate-buffered saline three times, then add 1 mL of The above-mentioned lower layer solution was then placed in an incubator at 37°C for 1 hour, and then the lower layer solution was removed from each well and washed three times with phosphate-buffered saline without rinsing the antibiotic. Stick the surface of the silicon chip to avoid washing away the blood attached to the anti-bioadhesive silicon chip, and then add 1 mL of glutaraldehyde solution (including glutaraldehyde and phosphate buffered saline) to each well. normal saline, and the concentration of the glutaraldehyde is 2.5wt%) and let stand for 3 hours, then remove the glutaraldehyde from each well and rinse with phosphate-buffered saline three times, then, use lens tissue Wipe dry to obtain the sample to be tested. Use an inverted fluorescence microscope system module (brand: Mshot Co.; model: MSG0) that includes an inverted phase-contrast fluorescent microscope (brand: Nexcope; model: NIB410) to observe and take pictures of the sample to be tested, and then , using Image J software to calculate the attached amount of red blood cells.
血小板貼附量量測：對健康的捐血者進行抽血作業，並將血液輸送至含有檸檬酸鈉(Sodium citrate)抗凝血劑的血袋中，獲得血液樣品。利用離心機對該血液樣品進行離心處理，且該離心處理的離心力為1500rcf及時間為10分鐘，並取出包含濃度為1×10 4count/μL以上的血小板的上層液。將尺寸為1cm 2的應用例1的抗生物沾黏矽晶片放置於24孔盤(well plate)中，接著，於每個孔中加入1mL的磷酸鹽緩衝生理鹽水(phosphate buffered saline)，然後，放入37℃的培養箱中靜置12小時，接著，自每個孔中移除磷酸鹽緩衝生理鹽水，然後，用磷酸鹽緩衝生理鹽水潤洗三次，接著，於每個孔中加入1mL的上述的上層液，然後，放入37℃的培養箱中靜置1小時，接著，自每個孔中移除該上層液，並用磷酸鹽緩衝生理鹽水潤洗三次，且不可沖洗到該抗生物沾黏矽晶片的表面，以避免將貼附在該抗生物沾黏矽晶片上的血液被沖刷掉，然後，於每個孔中加入1mL的戊二醛溶液(包括戊二醛及磷酸鹽緩衝生理鹽水，且該戊二醛的濃度為2.5wt%)並靜置3小時，接著，自每個孔中移除該戊二醛並用磷酸鹽緩衝生理鹽水潤洗三次，然後，利用拭鏡紙擦乾，獲得待測樣品。利用包含倒立相位差螢光顯微鏡(廠牌：Nexcope；型號：NIB410)的倒立式螢光顯微鏡系統模組(廠牌：Mshot Co.；型號：MSG0)對該待測樣品進行觀測及拍照，然後，利用Image J軟體計算血小板貼附量。 Platelet attachment measurement: Blood draws from healthy blood donors, and the blood is delivered to blood bags containing sodium citrate (Sodium citrate) anticoagulant to obtain blood samples. The blood sample was centrifuged with a centrifugal force of 1500 rcf for 10 minutes, and the supernatant containing platelets with a concentration of 1×10 4 count/μL or more was taken out. Place the anti-bioadhesion silicon chip of Application Example 1 with a size of 1 cm in a 24-well plate, then add 1 mL of phosphate buffered saline to each well, and then, Put it in an incubator at 37°C for 12 hours, then remove phosphate-buffered saline from each well, then rinse with phosphate-buffered saline three times, then add 1 mL of The above supernatant was then placed in an incubator at 37°C for 1 hour, and then the supernatant was removed from each well and rinsed three times with phosphate buffered saline without washing out the antibiotic. Stick the surface of the silicon chip to avoid washing away the blood attached to the anti-bioadhesive silicon chip, and then add 1 mL of glutaraldehyde solution (including glutaraldehyde and phosphate buffered saline) to each well. normal saline, and the concentration of the glutaraldehyde is 2.5wt%) and let stand for 3 hours, then remove the glutaraldehyde from each well and rinse with phosphate-buffered saline three times, then, use lens tissue Wipe dry to obtain the sample to be tested. Use an inverted fluorescence microscope system module (brand: Mshot Co.; model: MSG0) that includes an inverted phase-contrast fluorescent microscope (brand: Nexcope; model: NIB410) to observe and take pictures of the sample to be tested, and then , using Image J software to calculate the amount of platelet attachment.
水接觸角量測：將2μL的去離子水滴在應用例1的抗生物沾黏矽晶片的表面，然後，利用表面接觸角測量儀(廠牌：FIRST TEN ANGSTROMS；型號：FTA125)測量出水與該抗生物沾黏矽晶片的表面的夾角。Water contact angle measurement: 2 μL of deionized water was dropped on the surface of the anti-bioadhesive silicon wafer in application example 1, and then, the surface contact angle measuring instrument (brand: FIRST TEN ANGSTROMS; model: FTA125) was used to measure the relationship between the effluent and the The included angle of the surface of the anti-biostick silicon wafer.
表1
表2
綜上所述，透過該式(I)所示的結構單元及該式(II)所示的結構單元，本發明抗生物沾黏共聚物的醛基具有穩定性而不易產生自交聯反應，從而有利於接枝於表面具有胺基的基材上，以至於賦予該基材具有良好的抗生物沾黏性，故確實能達成本發明的目的。In summary, through the structural unit represented by the formula (I) and the structural unit represented by the formula (II), the aldehyde group of the anti-bioadhesive copolymer of the present invention has stability and is not prone to self-crosslinking reaction, Therefore, it is beneficial to graft on the substrate with amine groups on the surface, so as to endow the substrate with good anti-bioadhesive property, so the purpose of the present invention can indeed be achieved.
惟以上所述者，僅為本發明的實施例而已，當不能以此限定本發明實施的範圍，凡是依本發明申請專利範圍及專利說明書內容所作的簡單的等效變化與修飾，皆仍屬本發明專利涵蓋的範圍內。But the above-mentioned ones are only embodiments of the present invention, and should not limit the scope of the present invention. All simple equivalent changes and modifications made according to the patent scope of the present invention and the content of the patent specification are still within the scope of the present invention. Within the scope covered by the patent of the present invention.
本發明的其他的特徵及功效，將於參照圖式的實施方式中清楚地呈現，其中： 圖1是一紅外線光譜圖，說明本發明實施例1及實施例3的抗生物沾黏共聚物的結構；及 圖2是一核磁共振圖譜，說明本發明實施例1的抗生物沾黏共聚物的結構。 Other features and effects of the present invention will be clearly presented in the implementation manner with reference to the drawings, wherein: Figure 1 is an infrared spectrogram illustrating the structures of the anti-bioadhesive copolymers of Example 1 and Example 3 of the present invention; and FIG. 2 is a nuclear magnetic resonance spectrum illustrating the structure of the anti-bioadhesive copolymer of Example 1 of the present invention.
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